There are three types of opioid receptors (Mu (μ), Kappa (κ) and Delta (δ)), found to be expressed in both the CNS and in the periphery and the available opioid analgesics mediate their effects through these opioid receptors (Evans, C., Keith, J. D., Morrison, H., Magendzo, K and Edwards, R., Science, 258, 1952-1955, 1992; Cox, B. M., Mol. Pharmacol., 83, 723-728, 2013; Chen, Y., Mestek, A., Liu, J., Hurley, J and Yu, L., Mol. Pharmacol., 44, 8-12, 1993; Meng, F., Xie, G. X., Thompson, R., Mansour, A., Goldstein, A., Watson, S. J and Akil, H., Proc. Natl. Acad. Sci., U.S.A., 90, 9954-9958, 1993; Simonin, F., Gaveriaux, R. C., Befort, K., Matthes, H., Lannes, B., Micheletti, G., Mattei, M. G., Charron, G., Bloch, B and Kieffer, B., Proc. Natl. Acad. Sci., U.S.A., 92, 7006-7010, 1995; Stein, C., Anesth. Analg., 76, 182-191, 1993). Most of the opioid analgesics at present, for example, morphine, act by binding to the μ-opioid receptor, and their analgesic activity are associated with a spectrum of undesirable side effects, such as physical dependence, respiratory depression, urinary retention, constipation, euphoria/dysphoria and constipation (Pasternak, G. W., Clin. Neuropharmacol., 16, 1-18, 1993).
In recent years, considerable attention has been focused on the development of receptor selective κ-agonists as potent and efficacious analgesics devoid of the undesirable side effects of the μ analgesics (Barber, A and Gottschlich, R., Med. Res. Rev., 12, 525-562, 1992). Unlike agonist at δ and μ receptors, agonist at κ-opioid receptors does not elicit constipation and euphoria. The κ-opioid receptors are members of the superfamily of G protein-coupled receptors (GPCRs). Agonist binding to the κ-receptors, activates the intracellular associated Gi protein, which decreases Ca2+ channel conductance or inhibits adenylyl cyclase (AC) (Prather, P. L., McGinn, T. M., Claude, P. A., Liu-Chen, L. Y., Loh, H. H and Law, P. Y., Mol. Brain. Res., 29, 336-346, 1995).
κ-opioid agonists have been suggested to have potential for treatment of incisional/inflammatory pain, burn injury pain (Field, M. J., Carrell, A. J., Gonzalez, M. I., McCleary, S., Oles, R. J., Smith, R., Hughes, J and Singh, L., Pain, 80, 383-389, 1999), neuropathic pain (Catheline, G., Guilbaud, G and Kayser, V., Eur. J. Pharmacol., 357, 171-178, 1998), visceral pain including dysmenorrhea or gastrointestinal pain (Delgado Aros S., Chial H. J., Camilleri M., Szarka L. A., Weber F. T., Jacob, J., Ferber, I., McKinzie, S., Burton, D. D and Zinsmeister, A. R., Am. J. Physiol. Gastrointest. Liver Phsyiol., 284, G558-G566, 2002), Irritable bowel syndrome (IBS) (Dapoigny, M., Abitbol, J. L., Fraitag, B., Digest. Dis. Sci., 40, 2244-2249, 1995; Mangel, A. W., Bornstein, J. D., Hamm, L. R., Buda, J., Wang, J., Irish, W., Urso, D., Pharmacol. Ther., 28, 239-249, 2008), rheumatoid arthritis (Endoh, T., Tajima, A., Suzuki, T., Kamei, J., Suzuki, T., Narita, M., Tseng, L and Nagase, H., Eur. J. Pharmacol. 387, 133-140, 2000) and anti-pruritis effects (Peters, G and Gaylor, S., Clin. Pharmacol. Ther., 51, PPF-5, 1989). Walker et al., (Walker, J. S., Adv. Exp. Med. Biol., 521, 148-60, 2003) appraised the anti-inflammatory properties of kappa agonists for treatment of osteoarthritis, rheumatoid arthritis, inflammatory bowel disease and eczema.
Bileviciute-Ljungar et al., (Bileviciute-Ljungar, T. Saxne, and M. Spetea, Rheumatology, 45, 295-302, 2006) describe the reduction of pain and degeneration in Freund's adjuvant-induced arthritis by the kappa agonist U-50,488. Thus, the κ-receptors represent important therapeutic targets (Pan, Z. Z., Tershner, S. A., Fields, H. L., Nature, 389, 382-385, 1997; Chavkin, C., Neuropsychopharmacology, 36, 369-370, 2011).
κ-opioid receptors exist extensively in the central nervous system (CNS) and play important roles in many physiological and pathological functions. Inspite of such potential applications, clinical studies have shown that κ-receptor agonist elicit severe centrally mediated side effects generally described as “dysphoric actions” (Pfeiffer, A., Brantl, V., Herz, A and Emrich, H. M., Science, 233, 774-776, 1986), water diuresis (Dykstra, L. A., Gmerek, D. E., Winger, G and Woods, J. H., J. Pharmacol. Exp. Ther., 242, 413-420, 1987) and psychotomimetic effects (Rimoy, G. H., Wright, D. M., Bhaskar, N. K., Rubin, P. C, Eur. J. Clin. Pharmacol. 46 (3), 203-207, 1994). These side effects have apparently halted further clinical development for this class of compounds. Many studies have shown that opiates have peripheral analgesic effects, especially under inflammatory or hyperalgesic conditions (Barber, A and Gottschlich, R., Med. Res. Rev., 12, 525-562, 1992).
Agonist at κ-opioid receptors have been shown to produce analgesia and decrease inflammation in models of rheumatoid arthritis after local administration (Wilson, J. L., Nayanar, V and Walker, J. S., Br. J. Pharmacol., 118, 1754-1760, 1996). Restricted CNS penetration is a common strategy to reduce central side effects of drugs with beneficial peripheral actions. Attempts have been made to develop peripherally restricted κ-opioid agonists, such as ICI204448 (Shaw, J. S., Carroll, J. A., Alcoc, P and Main, B. G., Br. J. Pharmacol., 96, 986-992, 1989), GR94839 (Rogers, H., Birch, P. J., Harrison, S. M., Palmer, E., Manchee, G. R., Judd, D. B., Naylor, A., Scopes, D. I. C and Hayes, A. G., Br. J. Pharmacol., 106, 783-789, 1992), Cadila Healthcare Ltd., Novel Heterocyclic compounds as Kappa Opioid Agonist (WO2015/119660) and EMD61753/Asimadoline (Barber, A., Bartoszyk, G. D., Bender, H. M., Gottschlich, R., Greiner, H. E., Harting, J., Mauler, F., Minck, K. O., Murray, R. D., Simon, M and Seyfried, C. A., Br. J. Pharmacol., 113, 1317-1327, 1994).
Unfortunately, most of these compounds were discontinued in clinical trials either due to poor bioavailability, lack of efficacy or CNS side effects at analgesic doses (Barber, A and Gottschlich, R., Exp. Opin. Invest. Drugs, 6, 1351-1368, 1997). Asimadoline was designed and synthesized to differentiate itself from other reported peripheral KOR agonists such as ICI 204448, GR94839, and BRL 52974. Asimadoline is an amphiphilic molecule that contains a hydrophobic diphenyl methyl group and a hydrophilic hydroxyl group. Asimadoline successfully passed a phase II clinical trial for irritable bowel syndrome (IBS) indication/treatment and currently, it is under phase III clinical trial for the treatment of patients with diarrhea-predominant IBS (D-IBS).
CR665 and CR845 are tetrapeptides consisting of all D-amino acids that bind very potently and selectively to KOR. Dooley et al., (Dooley, C. T., Ny, P., Bidlack, J. M and Houghten, R. A., J. Biol. Chem., 273, 18848-18856, 1998) reported the discovery of tetrapeptide (FE200041/CR665) as a high affinity and selective κ-opioid agonist. The data demonstrate that FE200041 is a highly selective κ-opioid antinociceptive agent without CNS side effects at doses higher than efficacy doses. The peripheral antinociceptive actions of FE20041 suggest that it is possible to develop peripherally restricted opioid peptides for use in controlling pain. In Phase I study, CR845 appeared to be well tolerated with no signs of dysphoria or psychotomimetic effects. However, in Phase III study CR845 was on clinical hold due to hypematremia (elevated sodium level in blood).
Cara Therapeutics Inc., discloses synthetic peptide amide ligands as peripheral KOR agonist, useful for the treatment of pain and inflammation associated with a variety of diseases and conditions (WO99/32510; US2008/7402564; US2009/0075907; US2009/0156508; US2009/0264373; US2010/7727963; US2010/0075910; US2010/7713937; US2010/7842662; US2010/0029575; US2011/0118186; US2011/0257105; US2011/0212882; US2013/0012448; WO2007/139921; WO2008/060552; WO2013/184794; WO2015/065867 and US2015/0150935). Patent Application from Cara therapeutics (WO2008057608) discloses synthetic peptide amide compounds of the following general formula as κ-opioid receptors.
Wherein the moiety
                selected from        

Considering the potential of KOR agonist in controlling/preventing visceral pain, hyperalgesia, rheumatoid arthritic inflammation, osteoarthritic inflammation, IBD inflammation, IBS inflammation, ocular inflammation, otitic inflammation or autoimmune inflammatory conditions, we initially prepared few short-chain peptides (two compounds, as listed in WO2008/057608, Chart-1) and their analogs.

However, these synthetic peptides did not show potent in vitro kappa opioid receptor agonistic activity (EC50>10 nM concentration) or in vivo activity in the acetic acid induced writhing model (in vivo antinociceptive activity, ED50>3 mg/kg, iv dose). Surprisingly, certain bicycle containing peptides (such as, compounds 4, 5, 15, 16, 35, 36 and 37, listed in Table 1) showed potent in vitro KOR agonistic activity (EC50<100 pM concentration, Table-4) and in vivo efficacy, in the acetic acid induced writhing model (in vivo antinociceptive activity, ED50≤0.1 mg/kg, iv dose, Table 5). This clearly indicate that right end of the synthetic peptide (nitrogen containing bicyclic and bridged cyclic ring system) is one of the important factors required to provide potent in vitro KOR agonistic activity and in vivo antinociceptive activity, in this class of molecules.
We herein disclose series of novel short-chain peptides of the general formula (I), which are selective and peripheral KOR agonist, useful for the treatment or prevention of diseases in which the Kappa (κ) opioid receptors (KOR) are involved, such as treatment or prevention of visceral pain, hyperalgesia, rheumatoid arthritic inflammation, osteoarthritic inflammation, IBD inflammation, IBS inflammation, ocular inflammation, otitic inflammation or autoimmune inflammation.